Enhancing cognitive function in humans is a major target for drugs companies and the health industry. However, so far there has been very little success. Current techniques can be categorised as follows: a) fighting biochemical deterioration with age or disease; and b) identifying neurotransmitter systems or signal transduction that can enhance neuronal function.
AD is one of the most common forms of dementia. It is generally diagnosed in people over the age of 65 years, although early onset is possible. AD is a progressive and terminal disease, for which there is currently no cure.
The ability to form new and stable memories deteriorates with age and is a clear hallmark of different neurodegenerative diseases including AD and frontotemporal dementia. The vast majority of AD cases have complex etiology with multiple genetic and environmental factors influencing pathogenesis. Indeed, different animal models are used to study the complex biology underlying AD (Gotz & Ittner (2008) Nature Reviews Neuroscience 9, 532-544).
Control of mRNA translation is a major means for regulation of gene expression in responses to external stimuli presented by the changing environment. Translation regulation comprises three major steps: initiation, elongation and termination, where, in eukaryotes, the initiation phase is usually rate-limiting and serves as the target for regulation. Several major signal transduction cascades, including the mTOR and eIF2α pathways, regulate translation initiation in neurons and other cells. Translation regulation in neurons is particularly complex. Major components of the protein synthesis machinery, including ribosomes, translation factors and mRNA are present in dendrites and dendritic spines, and translation can be regulated differentially at the cell body, the synapse and post-synaptic components. Importantly, cellular stress and injury often lead to an increase in phosphorylation of initiation-related proteins such as eIF2α and to subsequent down-regulation of the translation initiation process. The effects of neuronal activity and of distinct neurotransmitter systems on these signalling cascades, and their role in learning and memory and neuronal plasticity are not fully understood.
Initiation factor eIF-2 is a protein synthesis initiation factor, the activity of which is reduced in a controlled way by phosphorylation of its alpha subunit (eIF-2α). It has previously been shown (Costa-Mattioli et al. (2007) Cell 129, 195-206) that heterozygous mice in which the phosphorylation site of eIF-2α was mutated (and thus phosphorylation of eIF-2α was reduced) had improved cognitive function.
Other recent publications of interest include: Belelovsky et al. (2005) European Journal of Neuroscience 22, 2560-2568; Banko et al. (2006) Neurobiology of learning and memory 87, 248-256; Antion et al. (2008) Learning and memory 15, 29-38; Costa-Mattioli et al. (2005) Nature 436, 1166-1173; Paccalin et al. (2006) Dementia and Geriatric Cognitive Disorders 23, 320-326; Chang et al. (2002) Neuroreport 13, 2429-2432; Page et al. (2006) Neuroscience 139; 1343-1354; Kim et al. (2007) Journal of Neuroscience Research 85; 1528-1537; Bullido et al. (2008) Neurobiology of Aging 29, 1160-1166; Davis et al. (1984) Psychological Bulletin 96, 518-559; Nguyen et al. (1994) Science 265, 1104-1107; and Schicknick et al. (2008) Cerebral Cortex 18, 2646-2658.
The above disclosures teach the genetic modification of animals to improve cognitive function. However, there are many difficulties and much expense associated with such techniques. These solutions are therefore not currently practical.